The objective of this proposal is to obtain radiobiological information on a range of xenografted human tumors and mouse normal tissues, with emphasis on the response to low dose-rate irradiation and the effects of combined drug treatment. The aims are both fundamental and applied. Low dose-rate irradiation (down to 1cGy/min) will be used to investigate the response of human tumor cells, and human and mouse normal tissue cells, seeking to discriminate between repaired and unrepaired damage. Comparisons will be made between human tumor types and between tumor and normal tissue types in their response to low dose-rate irradiation. The results will be analysed on the basis of repair models, seeking to deduce the kinetics of repair of potentially lethal damage. A major aspect of the proposal is to investigate the influence of drug treatment on the initial part of the cell survival curve, and on response to low dose-rate treatment. This will be done both in tumor and normal tissue systems. The choice of drugs will include a range of chemotherapeutic agents, some of which are known radiation repair modifiers, as well as radiosensitising and other drugs. The tumor studies will be made on human tumores established as xenografts, especially cervix carcinoma, melanoma, neuroblastoma, and bladder carcinoma. They will be treated in 3 situations: in vitro as dispersed cultures or as multicellular spheroids, and in vivo in the immune-deficient mouse. The normal tissue studies will be made on the mouse lung, intestine and testis. In addition, we will seek to set up cultures of normal human cells for comparative study of low dose-rate sensitivity. The applied objectives relate to the treatment of cancer by radiation and drug therapy. The project seeks to investigate the initial slope of the cell survival curve, and response to low dose-rate irradiation in a range of human tumor and normal tissue types. This will lead to predictions about the therapeutic value of low dose-rate irradiations, with and without modification by drugs.